Over 30 species representing 11 genera (among 85 total) of the plant family Amaryllidaceae have been employed in traditional treatments for human cancer. Such applications of certain Narcissus species were recorded as early as 200 B.C. (Pettit, G. R. et al., J. Nat. Prod. 1995, 58, 756-759; Pettit, G. R., et al., J. Nat. Prod., 1995, 58, 37-43.) The biologically active constituents of Amaryllidaceae species have been under investigation from at least 1877 following Gerrard's report on a component of Narcissus pseudonarcissus designated narcissia. (Gerrard, A. W., Pharm. J., 1877, 8, 214; Cook, J. W., In The Alkaloids, Manske, R. H. F.; Holmes, H. L., Ed.; Academic Press: New York, 1952; pp. 331.) Presently, some 48 alkaloids and carbostyrils bearing a variety of carbon skeletons have been isolated from Narcissus species. (Weniger, B., et al., Planta Med., 1995, 61, 77-79.) Of these, the isocarbostyrils narciclasine (1) and pancratistatin (2) have been found to display the most promising in vivo antineoplastic activities and a selection of other amaryllidaceae alkaloids have been shown to provide cancer cell growth inhibitory activity. (Pettit, G. R., et al., J. Nat. Prod., 1995, 58, 756-759; Pettit, G. R., et al., J. Nat. Prod., 1995, 58, 37-43; Pettit, G. R., et al., J. Org. Chem., 2001, 66, 2583-2587; Rigby, J. H., et al., J. Amer. Chem. Soc., 2000, 122, 6624-6628; Suffness, M., et al., In The Alkaloids, Drossi, A., Ed., Academic Press: New York, 1985; pp. 205-207; Youssef, D. T. A., et al., Pharmazie 2001, 56, 818-822.)
Pancratistatin (2), which we first discovered in Pancratium littorale (reidentified as Hymenocallis littoralis) and later in Narcissus species, has been undergoing extended preclinical development. (Pettit, G. R., et al., J. Org. Chem., 2001, 66, 2583-2587; Rigby, J. H., et al., J. Amer. Chem. Soc. 2000, 122, 6624-6628; Pettit, G. R., et al., J. Nat. Prod., 1995, 58, 756-759; Pettit, G. R., et al., J. Nat. Prod., 1995, 58, 37-43.) That very important initiative was greatly assisted by conversion of the sparingly soluble isocarbostyril to a 7-O-phosphate salt. (Pettit, G. R., et al., Anti-Cancer Drug Design 2000, 15, 389-395; Pettit, G. R., et al., Anti-Cancer Drug Design 1995, 10, 243-250.) The antimitotic activity of narciclasine (1) has been known for over 35 years. Subsequently, it was shown in U.S. National Cancer Institute research to be active against in vivo growth of the M5076 sarcoma and P388 lymphocytic leukemia. In addition, it was found to inhibit protein synthesis in Erlich asciter cancer cells. (Suffness, M., et al., The Alkaloids, Drossi, A., Ed., Academic Press: New York, 1985; pp. 205-207.) However, as with the closely related pancratistatin (2), the low solubility properties of narciclasine has contributed to the delay in its preclinical development. Most of the inventors' early investigation involving this potentially useful isocarbostyril have targeted its use as a starting point for a practical synthesis of pancratistatin (2) and for SAR purposes. (Pettit, G. R., et al., J. Org. Chem. 2001, 66, 2583-2587; Rigby, J. H., et al., Amer. Chem. Soc. 2000, 122, 6624-6628; Pettit, G. R., et al., J-C. Heterocycles 2002, 56, 139-155.) Disclosed herein a very convenient transformation of narciclasine (1) to water soluble cyclic phosphate prodrugs (3).